Malaria journal · 2025
High-throughput screening and meta-analysis for lead compounds in antimalarial drug discovery.
СтатьяМетаанализНазвание и аннотация: Перевод в очереди
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Van Truong Nguyen, Na Seok-Won, Park Ji Hoon, Nguyen Tuyet-Kha, Thau Nguyen Sy, Chu Thi-Thanh Hang, Sanaullah Bazgha, Venkataramaiah Ch, Han Jin-Hee, Na Sung-Hun, Park Won-Sun, Chun Wan-Joo, No Joo Hwan, Han Eun-Taek
Аннотация
BACKGROUND: The discovery of novel antimalarial drugs against Plasmodium falciparum has become globally urgent due to the consistent increase in mortality, morbidity, and drug resistance in endemic areas.
METHODS: Using an in-house library, novel antimalarial agents were identified through in vitro high-throughput screening (HTS) and meta-analysis. Hit compounds were selected from the primary HTS at 10 µM and confirmed in a dose-dependent manner to determine their IC₅₀ values. The identified hit molecules were further selected based on the following criteria: novelty, antimalarial activity (IC50), pharmacokinetic properties (Cmax and T1/2), mechanism of action, and safety (in vitro and in vivo) (CC50, SI, LD50, and MTD). In vitro and in vivo antimalarial activity against drug-sensitive and resistant strains (3D7, NF54 and K1, Dd2, Dd2-R539T (+), and CamWT-C580Y (+)) and the rodent Plasmodium berghei parasite-infected animal model, respectively, were subsequently used to validate hit compounds.
RESULTS: Based on the top 3% threshold, 256 compounds were selected for dose‒response curve analysis from the HTS. Among them, 110 compounds without published research related to Plasmodium and 157 compounds with IC50 values < 1 µM were identified. Further analysis confirmed 69 compounds with median lethal doses, maximum tolerated doses or treated doses greater than 20 mg/kg, 48 compounds with FDA approval, 29 compounds characterized by Cmax > IC100 and T1/2 > 6 h, and 38 compounds with a potential mechanism in Plasmodium. Next, 19 candidates were further evaluated for in vitro inhibition of drug-resistant parasites and inhibition in a mouse model of P. berghei parasites. Notably, three potent inhibitors were identified, exhibiting 95.9% and 81.4% suppression via oral delivery at a dose of 50 mg/kg ONX-0914 and methotrexate, respectively, and 96.4% suppression via intraperitoneal delivery at a dose of 20 mg/kg of an antimony compound. In addition, strong in vitro antimalarial activity was demonstrated against CQ- and ART-sensitive and resistant strains (IC50 < 500 nM).
CONCLUSIONS: Combining HTS and meta-analysis provides a robust method for screening antimalarial candidate compounds and identifying new hits with in vivo activity as candidates to treat drug-resistant malarial strains.
METHODS: Using an in-house library, novel antimalarial agents were identified through in vitro high-throughput screening (HTS) and meta-analysis. Hit compounds were selected from the primary HTS at 10 µM and confirmed in a dose-dependent manner to determine their IC₅₀ values. The identified hit molecules were further selected based on the following criteria: novelty, antimalarial activity (IC50), pharmacokinetic properties (Cmax and T1/2), mechanism of action, and safety (in vitro and in vivo) (CC50, SI, LD50, and MTD). In vitro and in vivo antimalarial activity against drug-sensitive and resistant strains (3D7, NF54 and K1, Dd2, Dd2-R539T (+), and CamWT-C580Y (+)) and the rodent Plasmodium berghei parasite-infected animal model, respectively, were subsequently used to validate hit compounds.
RESULTS: Based on the top 3% threshold, 256 compounds were selected for dose‒response curve analysis from the HTS. Among them, 110 compounds without published research related to Plasmodium and 157 compounds with IC50 values < 1 µM were identified. Further analysis confirmed 69 compounds with median lethal doses, maximum tolerated doses or treated doses greater than 20 mg/kg, 48 compounds with FDA approval, 29 compounds characterized by Cmax > IC100 and T1/2 > 6 h, and 38 compounds with a potential mechanism in Plasmodium. Next, 19 candidates were further evaluated for in vitro inhibition of drug-resistant parasites and inhibition in a mouse model of P. berghei parasites. Notably, three potent inhibitors were identified, exhibiting 95.9% and 81.4% suppression via oral delivery at a dose of 50 mg/kg ONX-0914 and methotrexate, respectively, and 96.4% suppression via intraperitoneal delivery at a dose of 20 mg/kg of an antimony compound. In addition, strong in vitro antimalarial activity was demonstrated against CQ- and ART-sensitive and resistant strains (IC50 < 500 nM).
CONCLUSIONS: Combining HTS and meta-analysis provides a robust method for screening antimalarial candidate compounds and identifying new hits with in vivo activity as candidates to treat drug-resistant malarial strains.